chapter 37
Mineral Metabolism
Ascorbic acid, increased intestinal pH, sulfide ion, phy-
tate (inositol hexaphosphate in plants), and some dietary
proteins interfere with its intestinal absorption.
Copper sulfate causes ulceration of the oral
esophageal mucosa, and an acute dose of 7-8 g is usually
fatal. Copper intoxication has occurred when copper salts
were used to treat extensive skin bums or when copper-
containing tubing or dialysis membranes were used for
hemodialysis. Pulmonary fibrosis has been described in
vineyard workers exposed for many years to fungicidal
sprays (e.g., “Bordeaux mixture”) containing copper sul-
fate. About 33-50 mg of copper per year (''-TOO /zg/d)
dissolves from copper-containing intrauterine contracep-
tive devices. Part of this copper is lost in menstrual flow,
but part is rapidly absorbed. Whether this is harmful is not
known but it seems unlikely. Penicillamine is the drug of
choice for treatment of copper excess.
The RDA for copper increases with age, ranging from
0.5-0.7 mg in infants up to
months of age to 2-3 mg
in adults. The average adult diet contains 2.5-5 mg/d.
Healthy, full-term infants have a relatively high hepatic
copper content. The lower copper content of premature
and malnourished infants is exacerbated by feeding with
cow’s milk, which contains less copper than human milk.
About 40-70% of ingested copper is absorbed. Appear-
ance in plasma of ingested copper with a peak occurring
1.5-2.5 hours after eating suggests that absorption begins
in the stomach and proximal small intestine. Absorption
may be inversely related to the metallothionein content
of the mucosa. Although pinocytosis occurs in the in-
testines of human infants, their inability to absorb copper
in Menkes’ syndrome suggests that physiologically im-
portant absorption is by an active process, even at an early
age. Absorption is enhanced by complex formation with
-amino acids and small peptides. Newly absorbed copper
is taken up by the liver in a saturable transport process and
secreted into plasma as ceruloplasmin (0.5-1.0 mg/d).
Copper is excreted in bile in an amount roughly equal to
daily absorption (~1.7 mg/d). Toxic levels in liver occur
in primary biliary cirrhosis, Indian childhood cirrhosis (a
familial, probably genetic, disease, limited to Asia), and
other liver diseases in which bile flow is disrupted. Toxicity
is rare unless there is preexisting liver disease or ingestion
of large amounts of copper salts. Biliary copper is in a
form that cannot be readily reabsorbed. Some loss also
occurs in urine and sweat. Renal copper reabsorption may
be important for copper homeostasis and may be regulated
by insulin or glucagon. Approximately 0.5 mg of copper is
lost during each menstrual period. During lactation, cop-
per loss averages 0.4 mg/d.
The biological functions of copper are mostly reflected
in the proteins listed in Table 37-5. Like iron, copper is
intimately involved in adaptation to an aerobic environ-
ment. The proteins contain copper bound directly to spe-
cific side chains. Copper is also essential in plants, lower
eukaryotic animals, and prokaryotes.
Wilson’s disease is an autosomal recessive disease of
copper metabolism. It has a prevalence of 1 in 30,000
live births in most populations. The disease has a highly
variable clinical presentation. It is characterized by im-
pairment of biliary copper excretion, decreased incorpo-
ration of copper into ceruloplasmin, and accumulation of
copper in the liver and, eventually, in the brain and other
tissues. The biochemical findings include low serum ceru-
loplasmin, high urinary copper excretion, and high hepatic
copper content. Some patients have normal serum cerulo-
plasmia levels, and heterozygous individuals do not con-
sistently show reduced levels of this protein.
The genetic defect in Wilson’s disease resides in the
long arm of chromosome 13 and the gene codes for a
copper-transporting ATPase. Thus far, more than 40 dif-
ferent mutations have been found. The defect in the AT-
Pase results in reduced biliary excretion of copper from
the hepatocytes. The end result may lead to hepatic fail-
ure. The Cu-ATPase belongs to a family of ubiquitous
proteins that are involved in the translocation or move-
ment of cations such as H+, Na+, K+, Ca2+, and other
metal ions (discussed in the appropriate areas of the text).
This family of ATPases is designated as P-type ATPase.
The P designation stems from the fact that, during the
catalytic cycle, an invariant aspartic acid residue under-
goes phosphorylation by ATP and dephosphorylation by
the phosphatase domain that results in a conformational
change promoting cation transfer. Another common fea-
ture of P-type ATPase is that all possess an ATP binding
domain at the carboxy terminus. Because intestinal copper
absorption is unaffected, there is a net positive copper bal-
ance. Normal hepatic copper uptake ensures that copper
accumulation occurs first in the liver. As the disease pro-
gresses, nonceruloplasmin serum copper increases, and
copper deposits occur in various tissues, e.g., Descemet’s
membrane in the cornea (Kayser-Fleischer rings), basal
ganglia (leading to lenticular degeneration), kidney, mus-
cle, bone, and joints. Cultured fibroblasts from patients
exhibit increased copper uptake. A disorder in Bedling-
ton terriers that causes hepatic copper accumulation may
serve as an animal model for Wilson’s disease, although
it differs from the human disorder in several ways.
Penicillamine, a chelating agent, solubilizes copper and
other heavy metals and promotes their excretion in urine,
analogous to the use of deferoxamine in the treatment
of iron overload (Chapter 29). Long-term treatment with
penicillamine increases the requirement for pyridoxine.
Iron supplements should also be given, on a schedule
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